We propose to define the complex role of genes within the major histocompatability complex (MHC) region on chromosome 6p21 in rheumatoid arthritis (RA) pathogenesis. Our study design is based on the overall hypothesis that complex genetic and non-genetic MHC related mechanisms, including effects conferred by classical HLA loci, contribute to disease risk and clinical outcome. It is clear that the genetic contribution of the MHC to RA is substantial, with HLA-DRB1 alleles encoding the RA "shared epitope" demonstrating the most prominent association. However, previous research supports the presence of additional, possibly interacting, susceptibility loci within the MHC. Further, the extensive linkage disequilibrium in the region and incomplete knowledge of allelic variation in surrounding genes has been a major limiting factor in attempts to further define the genetic contribution of the MHC to RA. Through the recent efforts of the MHC Haplotype Project, all genes encoded within the -4.5 Mb MHC region have been identified and localized, and are now publicly available, providing an unparalleled molecular guide for deciphering the MHC contribution to RA. It is also evident that additional mechanisms such as genomic imprinting and non-inherited or environmental influences are likely to be involved in susceptibility to complex diseases such as RA. Using 1,000 stringently ascertained and clinically characterized RA families, state of the art genotyping methodologies, and novel analytical approaches we propose for the first time a comprehensive study of all genes residing within the MHC. In addition, we will investigate potential imprinting and maternal-fetal relationships in these families to determine whether MHC encoded loci and specific HLA alleles or haplotypes influence the risk of RA. These studies will unequivocally identify the genes and allelic variants residing in the MHC region involved in susceptibility to RA. Finally, due to the clinical and apparent genetic heterogeneity of RA, we will study specific RA phenotypes as secondary outcomes.